The formation of coronary artery disease that blocks blood circulation is closely related to the high levels of low density lipoprotein (LDL) in the blood (Goodman and Gilman, the Pharmacological Basis of Therapeutics, Page 879 (9th Edition, 1996)). At present, statins are the most effective drugs to reduce the concentration of LDL particles in the blood for patients having the risk for cardiovascular disease, and therefore they are used for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis, etc. Statins inhibit the biosynthesis of cholesterol by their competitive inhibition to 3-hydroxyl-3-methyl-glutaryl coenzyme A (“HMG-CoA”) reductase, which results in reduction in the concentration of LDL particles in the blood, and therefore reduces the possibility of suffering from coronary artery disease (J. A. M. A. 1984, 251, 351-74).
At present, there is a number of statins with different structures available in the market, including Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Cerivastatin, Atorvastatin, Rosuvastatin and Pitavastatin, etc. As a HMG-CoA reductase inhibitor, Rosuvastatin calcium (that is, (E)-7-[4-(4-fluorophenyl)-6-isopropyl]-2-[methyl(methyl sulfonyl)amino]pyrimidyl-5-(3R,5S)-3,5-dihydroxy-6-heptenoic calcium) is a so-called super statin, and compared with the first generation statins, Rosuvastatin calcium is more effective in reducing the concentration of LDL-cholesterol and triglyceride in vivo.
The commercial name of Rosuvastatin is CRESTOR, and it should be taken orally once per day for the treatment of hyperlipoidemia (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, Feb. 8, 1999 and Feb. 25, 2000). The daily dosage can be about 5 mg to about 40 mg. As for patients who do not require a considerable reduction of LDL-C or patients who have predisposing factors of myonosus, the recommended dosage is 5 mg, as for common patients, the recommended dosage is 10 mg, as for patients who have hyper cholesterolemia and require a relatively high lipid target (>190 mg/dL), the recommended dosage is 20 mg, while for patients who do not show response at low dosage, the recommended dosage is 40 mg. Rosuvastatin Calcium could also be used for the treatment of hypercholesterolemia, hyperproteinemia and atherosclerosis.
Synthesis and preparation of Rosuvastatin calcium was first disclosed in EP 0521471, wherein 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-5-pyrimidinecarbaldehyde and Methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate reacted and refluxed in the presence of acetonitrile, subsequently, silyl group underwent pyrolysis under the action of HF, the obtained compound was reduced by NaBH4, as a result, Rosuvastatin methyl ester was formed. Said ester was hydrolyzed by NaOH at room temperature in the presence of ethanol, at the end of the reaction, ethanol was removed, ether was added and Rosuvastatin sodium was obtained. The obtained Rosuvastatin sodium was dissolved in water under a nitrogen atmosphere. CaCl2 was added to said water solution, and precipitate of Rosuvastatin calcium was obtained. Wherein, the method disclosed by said patent required column chromatography to be carried out, which leads to increase in the complexity of process and production cost, and therefore it is not conducive to the goal that reducing the medical cost to benefit more patients. Bioorganic & Medicinal Chemistry, Vol. 5, NO. 2, pp 437-444, 1997 also reported a synthetic method of Rosuvastatin calcium, and said method was similar to that disclosed in EP0521471.
In EP0521471, even after column chromatography, the obtained Rosuvastatin methyl ester was still syrupy, this syrupy Rosuvastatin methyl ester was difficult to be purified by recrystallization, its purity was lower than 97% and the content of diastereomer was above 5%. EP0521471 described the formation of Rosuvastatin sodium via hydrolysis in ethanol, the obtained was beat with ethyl ether and crystallized Rosuvastatin sodium crystal powder was obtained, however, the formation of crystallized solid powder could only be realized in the laboratory by beating with ethyl, and it was very difficult to scale up and be applied to large-scale industrialized production, furthermore, the purification effect is not satisfactory due to the fact that diastereomer could not be separated by this process. EP0521471 disclosed the direct synthesis of Rosuvastatin calcium from Rosuvastatin sodium, however, these steps make the calcium salt difficult to be purified by recrystallization of Therefore, the content of diastereomer in Rosuvastatin calcium obtained from Rosuvastatin methyl ester was around 0.8%, several unknown impurities with concentration of above 0.1% were observed, leading to difficulty in obtaining highly purified Rosuvastatin calcium and industrialization of Rosuvastatin calcium. Furthermore, since the compound of Formula 3 presented in said EP0521471 and its improved method is taken in excess, the utilization rate of high cost compound as shown in Formula 3 was lower than 50% and the production cost was strongly affected. Accordingly, it is required to purify the compound as shown in Formula 4 or compound as shown in Formula 5 by column chromatography in current technique, otherwise purification is very difficult to be realized via direct recrystallization. However, the production cost of column chromatography is high and it is difficult to be applied in industrialization.
Improvements of synthetic process of EP0521471 have been reported. For instance, international application WO03087112 improved phosphorus ylide reagent based on EP0521471, wherein diester glutarate was converted to monoester glutarate via biological enzyme method, subsequently, the resultant was converted into tert-butyl ester containing silane blocking group, as a result, phosphorus ylide reagent different from that of EP0521471 in term of ester group was obtained; WO03097614 disclosed improvement of synthetic process of main-chain aldehyde N-[4-(4-fluorophenyl)-5-formyl-6-(1-methylethyl)-2-pyrimidyl]-N-methyl-methansulfnamide, however, preparation method of final product was similar to EP0521471; international application WO2005023778 reported industrial preparation method of Rosuvastatin calcium in substance free of impurities, however, the synthesis method of Rosuvastatin ester was still similar to that disclosed in EP0521471, furthermore, no detailed information was available on how to prepare highly purified Rosuvastatin ester; international application WO2006091771 described improvement of synthesis of Rosuvastatin calcium, wherein the major difference between WO2006091771 and EP0521471 was that ester group of side chain was replaced by ter-butyl ester group, but it was still very difficult to prepare highly purified Rosuvastatin according to the method of said application.
Besides preparation methods based on EP0521471, other synthetic methods which are different from the synthetic route of EP0521471 have been reported as well. For instance, international application WO0049014 (priority date: Feb. 17, 1999) reported a preparation method of Rosuvastatin calcium. Wherein, tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate with two chiral centers was acted as side chain, said chain reacted with phosphorus ylide reagent diphenyl[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-ylmethyl]phosphine oxide and took place Wittig condensation, subsequently, acetonylidene blocking group was removed via acidic hydrolysis, the obtained was saponified in the presence of alkali, in this way, sodium salt was converted to calcium salt.
EP1035127 disclosed a preparation method of intermediate of Rosuvastatin calcium, wherein said intermediate can be used in the synthetic route of WO0049014; WO2004108691 described improvement of the formation of Rosuvastatin salt from Rosuvastatin calcium, however, said improvement was based on the preparation method of Rosuvastatin calcium reported in WO0049014; international application WO2005042522 reported a preparation method based on WO0049014, wherein the crystallized intermediate was separated and used for the synthesis of Rosuvastatin.
Furthermore, improvements of the synthesis of Rosuvastatin calcium and its intermediate have been reported. For instance, international application WO0042024 focused on some specific crystal forms of Rosuvastatin calcium; international applications WO0154668 and WO0154669 disclosed a composition of Rosuvastatin calcium; international application WO0160804 described crystalline salt of Rosuvastatin, wherein said crystalline salt could be used for the purification of Rosuvastatin calcium; international application WO0241895 disclosed the use of Rosuvastatin in the treatment of an indication, that is heterozygous familial hyperlipidemia; international application WO2004014872 described improvements of the salt formation of Rosuvastatin calcium, wherein the improved processing conditions were used for preparation of highly filtrated solid; international application WO2004103977 disclosed improvement of synthesis of pyrimidyl heterocycle intermediate of Rosuvastatin calcium; international application WO2007000121 reported improvement on the preparation of Rosuvastatin calcium from Rosuvastatin lactone intermediate; international application WO2006079611 described other crystal forms of Rosuvastatin calcium (crystal form B and C); Chinese patent application CN1872841 disclosed recrystallization method of compound as shown in Formula 5, wherein said compound was recrystallized under the action of mixed solvent containing methylbenzene and ethyl ether, as a result, intermediate with purity of higher than 98% was obtained, however, Rosuvastatin methyl ester still required to be purified by column chromatography, the purity of said Rosuvastatin methyl ether was very low, the content of diastereomer was 0.5% and the total content of other impurities was 1%; international application WO2006136408 reported a preparation method of Rosuvastatin calcium and other Rosuvastatin salt from Rosuvastatin ester; international application international application WO2007022488 reported crystalline intermediate of Rosuvastatin and a process for the preparation thereof.